Translational relevance of HER2-low expression in triple-negative breast cancer: A retrospective single-center study.
Authors: Suhail Sayeed Mufti, Niyati Sanghavi, Veena Ramaswamy, Radheshyam Naik, Basavalinga Sadasivaiah Ajaikumar
Journal: Journal of Clinical Oncology (2022)

e13061 Background: In current clinical practice, the decision of using anti-HER2 targeted agents for breast cancer is based primarily on HER2 protein overexpression, assessed using immunohistochemistry and/or HER2 gene amplification on FISH assay(2018 ASCO/CAP guidelines). It is increasingly being recognized that HER2-negative breast cancer is characterized by a wide spectrum of HER2 expression, particularly important for the triple-negative breast cancer (TNBC) group, the treatment options for which are far less compared to hormone receptor-positive tumors. HER2-low breast cancer (HER1+ or 2+, without gene amplification) is an emerging subtype with differing clinicopathologic and prognostic implications. There is accumulating evidence that HER2-negative tumors may switch to HER2-low status and vice versa at tumor recurrence. The development of newer drug classes like antibody-drug conjugates and immunotherapy have created a window of opportunity for this sub-category of breast cancer. Methods: We aimed to evaluate HER2 0/normal and HER2-low expression in TNBCs, their clinicopathological characteristics, and prognostic significance. Clinical and laboratory data for 207 TNBC cases (184 non-metastatic and 23 metastatic) diagnosed between February 2010 and December 2019 was available for analysis and cases were followed up until December 2021. Androgen receptor (AR) immunohistochemistry was performed on available FFPE blocks. Results: Non-metastatic TNBCs: Median age was 50 (SD 11.77; range 23 to 82) years. 91.9% of HER2-low cases were more than 40years old compared to 70.1% of HER2 0 cases, p = 0.006. 79.9% were HER2 0, 14.1% were HER2 1+, and 6% were HER2 2+. 30.7% (39/127) of cases were AR+. Compared with HER2 0, HER2-low cases exhibited a lower histological grade (Her2 0 - Grade 3: 72.7%, Grade 2: 27.3%; Her2-low- Grade 3: 57.1%, Grade 2: 40%, Grade 1: 2.9% p=0.048). Compared with HER2 0, more of HER2-low cases were AR+ (For Her2 0 26.5% were AR+; For Her2-low 48% were AR+, p=0.036). There was no significant difference in disease-free survival between the two groups. There was no significant difference in overall survival (OS) between the two groups (Her2 0- Mean: 102.0 months, Median: Not achieved; Her2-low - Mean: 69.60 months, Median: 77.4 months p=0.73). Within the Her2-low group, patients ≤40 years had a median OS of 44.3 months. Metastatic TNBCs: Median age was 47 (SD 10.38; range 30 to 74) years. There was no significant correlation between the clinicopathological characteristics. No significant difference in OS was seen (Her2 0- Median: 44.9 months; Her2-low- Median: 24.3 months, p=0.20). Conclusions: The non-significant trend towards a lower survival for Her2-low TNBCs, coupled with a surprisingly lower histologic grade and a higher AR positivity needs to be further evaluated in larger studies. Further translational research to optimize treatment for this subgroup is needed.